Comparison of Diazeniumdiolated Dialkylhexanediamines as Nitric Oxide Release Agents on Nonthrombogenicity in an Extracorporeal Circulation Model

When blood from a patient is circulated through extracorporeal circuits (ECCs), such as in cardiopulmonary bypass or extracorporeal life support, platelets in the blood are activated and form a thrombus. This is prevented clinically with a range of different systemic anticoagulation agents (e.g., heparin); however, this increases a patient’s risk of hemorrhage. Previous work with nitric oxide (NO) releasing materials using the combined diazeniumdiolated diamine, N – N -di- N ′-butyl-1,6-hexanediamine (DBHD), and a polymer-linked thrombin inhibitor, argatroban (AG), showed significant nonthrombogenicity in ECCs using a 4 h rabbit model. Herein, we evaluated if diazeniumdiolated N – N -di- N ′-propyl-1,6-hexanediamine (DPHDN 2 O 2 ), which has a slightly lower degree of lipophilicity compared to DBHDN 2 O 2, would provide similar nonthrombogenicity as the AG/DBHDN 2 O 2 -polymer-coated circuits. While DPHDN 2 O 2 releases NO at a higher flux rate than DBHDN 2 O 2 when coated (within CarboSil polymer) on the inner wall of polyvinyl chloride tubing, neither coated circuit significantly affected animal hemodynamics. Both diazeniumdiolated diamines, in combination with immobilized AG or alone, significantly reduced thrombus formation similarly in the 4 h rabbit model (vs uncoated control): AG/DBHDN 2 O 2: 0.12 ± 0.03 cm 2; DBHDN 2 O 2: 2.57 ± 0.82 cm 2; AG/DPHDN 2 O 2: 0.68 ± 0.22 cm 2; DPHDN 2 O 2: 1.87 + 1.26 cm 2; uncoated control: 6.95 ± 0.82 cm 2 . AG/DPHDN 2 O 2 was no different than AG/DBHDN 2 O in preserving platelet count and function. In addition, AG did not leach into the systemic circulation as the total clotting times were insignificantly different from the baseline values (AG/DPHDN 2 O 2: 12.7 + 0.5 s ( n = 3); AG/DBHDN 2 O 2: 12.3 + 0.7 s ( n = 3); baseline: 13.9 + 0.3 s ( n = 13)). Based on these results, both DPHDN 2 O 2 and DPHDN 2 O 2 are good candidates as NO donor molecules for creating nonthrombogenic polymer coatings for ECCs.